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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Amino Acids Esters of Acyclovir-Synthesis and AntiviralActivityIvanka Stankova 1 , Stoyan Shishkov 2 , Kalina Kostova 2 ,Daniel Todorov 2 , Luchia Mukova 3 , and Angel Galabov 31 Department of Chemistry, South-West University “Neofit Rilsky”, Blagoevgrad,Bulgaria; 2 Laboratory of Virology, Faculty of Biology, University of Sofia "St. Kl.Ohridski“, Sofia, Bulgaria; 3 The Stephan Angeloff Institute of Microbiology, BulgarianAcademy of Sciences, 1113, Sofia, BulgariaIntroductionFollowing the discovery of the first effective antiviral compound (idoxuridine) in 1959,nucleoside analogues, especially acyclovir (ACV) for the treatment of herpesvirusinfections, have dominated antiviral therapy for several decades [1,2]. However, ACV andsimilar acyclic nucleosides suffer from low aqueous solubility and low bioavailabilityfollowing oral administration. Derivatives of acyclic nucleosides, typically esters, weredeveloped to overcome this problem and valacyclovir, the valine ester of ACV, was amongthe first of a new series of compounds that were readily metabolized upon oraladministration to produce the antiviral nucleoside in vivo, thus increasing the bioavaililityby several fold [3,4].One of the known approaches in the treatment of viral infection is the application of anumber of combinations of specific inhibitors with different mechanism of action, so thesimultaneous use of inhibtors with immunomodulators. This action leads to reducing thedose of the drug and its resistance. There are distinct effects of combinations of acyclovir(9-(2-hydroxyethoxymethyl)guanine) and cisplatin, rimantadine and ribavirin, oseltamivirand rimantadine. А significant synergy between ribavirin and oseltamivir against influenzavirus H9N2 in vivo is established [5-7].We expect that the obtained new analogues by coupling of acyclovir with 4-F-Phenylalnine (R,S) could possess a greater antiviral effect due to synergy. A two newanalogues of acyclovir and 4-F-Phenylalnine (R,S) were synthesized and screened for theiractivity in vitro against herpes simplex virus-1 (HSV-1) and influenza virus.Results and DiscussionSynthesis of acyclovir analoguesA mixture of 1 a-b and DDC in dimethylformamide (DMF) was stirred for 1h at 0°C undernitrogen atmosphere. A solution of acyclovir (Figure 1) and 4-N,N-(dimethylamino)-pyridine (DMAP) was added to the reaction mixture and stirred for 24h. Then DMF wasevaporated in vacuo and the residue was chromatographed on silica gel. The resulting whitesolid, Boc–(4-F)-Phe–ACV (R, S) was dissolved in 20 ml of TFA and stirred at 0°C for 1hto remove the Boc group. Following removal of the TFA in vacuum, 20 ml of ethyl acetatewas added to the oily reside. The solution was then added drop-wise to the cold diethylether. After filtration, 4-F-Phe–ACV (R,S) (TFA salt) was collected as white solid withhigh purity (>95%). Four milliliters of triethylamine (TEA) was added to 4-F-Phe–ACV(R,S) and kept for 15 min before dissolving it in 15 ml DMF. The 1 H and 13 C-NMR, massspectrawere consistent with desired structure (2 a-b).FBoc-AA1 a-biiiFCONH 2O2 a-bONNONNHNH 2(i) acyclovir / DCC/DMAP ; (ii) TFA/CH 2CH 2Protected AA: 1 a) Boc-(4-F)-Phenylalanine (R);1 b) Boc-(4-F)-Phenylalanine (S).Fig. 1. Synthesis of acyclovir analogues with 4-F-Phenylalanine (R,S).Figure 1. Synthesis of acyclovir analogues with 4-F-Phenylalanine (R, S)528